Sirt1, an NAD-dependent protein deacetylase has emerged as important regulator of mammalian transcription in response to cellular metabolic status and stress. SIRT1 protects from Wallerian degeneration and protects against neurodegeneration in models of Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's and Parkinson's disease. The fact that Sirt1 protects in various disease models suggests a more general function of Sirt1 in normal and abnormal neuronal function. However, normal function of Sirt1 in neurons remains largely unknown. As part of our initial effort to defin the physiological function of Sirt1 in CNS, we found that SIRT1 deacetylates TORC1 (Transducer of Regulated CREB activity) and activates CREB mediated transcription. As coactivator of CREB, TORC1 regulates transcription of a number of important genes that have been implicated in the pathogenesis of neurodegenerative disorders, such as PGC-1alpha and BDNF. TORC1 regulates neuronal activity-dependent CREB transcription and we hypothesize that Sirt1 plays a role in this process. Since TORC1 is only expressed in CNS and testis, it potentially represents a unique target of neuronal Sirt1 function. However, it is likely that Sirt1 regulates other targets in neurons, especially in light of the fact that more than forty targets of Sirt1 have been identified in non-neuronal systems. We found that Sirt1 deactylase activity was inhibited by mutant huntingtin. This inhibition presumably leads to deregulation of numerous targets of Sirt1 in HD brain. We propose to examine the role of Sirt1 and its targets in normal and HD neurons. Neuronal activity-dependent regulation gene expression will be assessed in primary neurons in the presence or absence of Sirt1. TORC1-dependent expression profiles will be compared with Sirt1 profiles. We will also examine if higher levels of Sirt1 overexpression afford dose-dependent neuroprotection in HD-like mice. Unbiased and biased studies will be performed to examine Sirt1 targets in HD pathogenesis. More generally, this work will further our understanding of the precise mechanistic link between the sirtuins and healthy brain aging, and potentiate development of drugs that delay and ameliorate neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: We propose a research project to accelerate the pre-clinical validation of sirtuins as therapeutic targets for HD. These studies will also examine Sirt1-mediated regulation of transcriptional networks in normal and diseased brain. If successful, this approach will have high impact for HD as well as other neurodegenerative disorders.